Treatment of erectile dysfunction

ABSTRACT

Erectile dysfunction, particularly impotence, priapism and Peyronie&#39;s disease is treated by the transurethral administration of a therapeutically effective agent. The agents are administered to the urethra by means of a penile insert (1) having a rapidly releasing coating (4) containing the agent on its exterior surface or by means of an inserter (27) carrying an agent containing dose of agent (31) which can be displaced into the urethra.

This is a continuation of application Ser. No. 08/486,727, filed 7 Jun.1995, now abandoned, which is a division of application Ser. No.08/093,545 filed 19 Jul. 1993, now U.S. Pat. No. 5,474,535, which is adivision of application Ser. No. 07/787,306, filed 30 Oct. 1991, nowU.S. Pat. No. 5,242,391, which is a continuation-in-part of applicationSer. No. PCT/US91/02758, filed 22 Apr. 1991, which is acontinuation-in-part of application Ser. No. 07/514,397, filed 25 Apr.1990 now abandoned.

TECHNICAL FIELD

This invention relates to the treatment of erectile disfunction moreparticularly to the treatment of impotence, priapism and Peyronie'ssyndrome.

BACKGROUND OF THE INVENTION

As used herein, the term "erectile dysfunction" refers to certaindisorders of the cavernous tissue of the penis and the associated faciawhich produce impotence, the inability to attain a sexually functionalerection; priapism, the persistent and often painful erection of thepenis; and Peyronie's syndrome, a condition characterized by fibrosis ofthe cavernous tissue and associated painful and distorted erection ofthe penis. Erectile dysfunctions, particularly impotence, affect asubstantial number of patients. For example, impotence is estimated toaffect approximately 10 million American men and can result from any ofnumerous physiological or psychological factors which cause the bloodflow to and from the penis to remain in balance thereby preventingretention of sufficient blood to cause rigid dilation of the corpuscavernosa and spongiosa. As used herein, the term "impotence" is used inits broadest sense as the inability to attain a sexually functionalerection when desired.

Treatments for impotence include psychosexual therapy, hormonal therapy,administration of vasodilators such as nitroglycerin and α-adrenergicblocking agents (hereafter "α-blockers"), vascular surgery, implantedpenile prostheses, vacuum devices and external aids such as penilesplints to support the penis or penile constricting rings to alter theflow of blood through the penis. See Robert J. Krause, et al.,Impotence, N. Eng. J. Med. Vol. 321, No. 24, Dec. 14, 1989 for a generaldiscussion of the current state of the art.

Originally Dr. Latorre and later Dr. R. Verag of Paris demonstrated thatimpotence could be physiologically treated by the direct injection of avasoactive drug into a patient's epigastric artery and thereafterthousands of patients have treated their impotence by self injection ofsuch drugs directly into the corpora cavernosa. Forward, 1^(er)Symposium International Sur L'Erection Pharmacologigue, 17-19 November1989, Paris, p 2; R. Virag, et al, Intracavernous Injection ofPapaverine as a Diagnostic and Therapeutic Method in Erectile Failure,Angiology, 35, pp 79-87, 1984; (See also, U.S. Pat. Nos. 4,127,118,4,766,889 and 4,857,059 which are incorporated herein by reference). Thedrugs most commonly used include α-blockers, such as the long actingphenoxybenzamine and the short acting phentolamine, smooth musclerelaxants such as papaverine, prostaglandins having a vasoactivefunction such as prostaglandin-E₁ (PGE₁) and combinations of such drugshaving different receptor effects to enhance therapy. Erection producingintracavernous injection doses of papaverine are typically in the rangeof about 7.5 to 160 mg, of phentolamine are in the range of about 0.1 to10 mg of and of PGE₁ are in the range of about 2.5 to 50 micrograms. Seefor example, Kurkle, et al, Injection Therapy for Impotence Urol. Clin.of America, Vol. 15, No. 4, Nov. 88, pp 625-629 and N. Ishii, et al,Intra Cavernous Injection of Prostaglandin E for the Treatment ofErectile Impotence, J. of Urol., Vol. 141, February 1989, pp 323-325.Vasoactive intestinal peptides at doses of 10-100 μg have also beenreported as producing erection on intracavernous injection. See also, H.Handelsman, Diagnosis and Treatment of Impotence, U.S. Dept. of HealthServices, Agency for Health Care Policy and Research, April 1990, for asummary of intracavernal injection and other treatment of impotence.

Although intracavernous injection of vasoactive drugs can produce arelatively rapid onset of erection in patients suffering from impotenceattributable to venous leakage or arterial insufficiency; patients oftenfind the injections psychologically disturbing, painful, traumatic orinconvenient as evidenced by a high discontinuance rate. See S. Althouf,et al, Why Do So Many People Drop Out From Auto-Injection Therapy forImpotence?, Journal of Sex & Marital Therapy, Vol. 15, No. 2, 1989, pp121-129. Adverse side effects including priapism, corporeal nodules anddiffuse fibrosis, drug tolerance, bruising and hematomas. Swelling andulceration of penile skin at the injection site have also been reported.

Nevertheless, because of the relatively innocuous intervention involvedand the high failure rate of penile prostheses, the pharmacologicalapproach to the treatment of impotence is still quite advantageous to alarge number of patients and could be even more so if the side effectscould be avoided. The administration of vasodilators via the maleurethra has been disclosed in Voss, U.S. Pat. No. 4,801,587 and Kock,EPA 0357581 to produce erections as has the transurethral administrationof testosterone, S. M. Milco, Bulletins et Memoirs de la SocietaRoumaine D'Endocrinologie, Vol. 5, pp 434-437 (December 1939),strychnine and another drug (citation to be provided). It has also beensuggested that cocaine administered transurethrally could contribute toan erection although the reported side effects were catastrophic, JAMA,Vol. 259, No. 21, page 3176 (1988).

Priapism is less common than impotence and can be attributed to variouscauses. It has been associated with diseases producing intravascularagglutination or sludging, such as leukemia, and pharmacologicalpriapism has been reported in a small percentage of patients who aretreated for impotence by intracavernous injection. Priapism has beentreated by intracavernous injection of vasoconstrictors such asα-adrenergic receptor agonists (hereafter "α-agonist"). The reportedeffective doses of the α-agonist, phenylephrine, are in the range ofabout 0.1 to 2 mg.

Peyronie's syndrome is a condition of unknown etiology characterized byfibrosis of the cavernous tissues and painful and distorted erections.The current treatment consists of injection of steroids and otheranti-inflammatory agents into the site of the fibrosis.

With respect to administration of drugs directly to the penis, medicatedcatheters such as described in U.S. Pat. No. 4,640,912 have been used toprevent or treat localized infections and irritation of the urethra andbladder; a nitroglycerin coated, erection inducing condom is disclosedin U.S. Pat. No. 4,829,991; the transurethral administration of certaindrugs is suggested in U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and4,746,508; and medicated urethral suppositories, inserts or plugs,typically containing anti-infective agents or spermicides are disclosedin U.S. Pat. Nos. 1,897,423, 2,584,166, 2,696,209 and 3,373,746, forexample. As noted above, Voss, Kock, Milco, and others discloseintroducing agents into the urethra to induce erections.

According to our invention, we have provided methods and dosage formsfor the treatment of erectile dysfunctions which are painless, capableof rapidly, safely and effectively producing erection of the penis inthe case of impotence, detumescence of the penis in the case of priapismand administration of anti-inflammatory drugs to fibrotic sites in thecase of Peyronie's syndrome without the above described adverse sideeffects and with a high degree of patient acceptability.

BRIEF DESCRIPTION OF THE INVENTION

We have found that the above-described erectile dysfunctions can besafely and effectively treated by the transurethral administration ofthe appropriate therapeutic drug or combination of therapeutic drugs (asused herein the term "agent" refers to a drug or a combination of drugscapable of producing the desired therapeutic effect) and have providedcompositions and penile inserts adapted to be easily and painlesslyinserted into the urethra, which compositions or inserts carry theappropriate therapeutic agent in an amount sufficient to produce thedesired result.

In one preferred embodiment of this invention the therapeutic agent isapplied as a coating on a penile insert configured to prevent completeinsertion and to facilitate removal.

In another preferred embodiment of this invention, the agent iscontained in a gel, cream, ointment or suppository for example which maybe deposited in the urethra from a specially designed inserter.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention and the advantages thereof will be readily apparent fromthe following description of the invention with reference to theaccompanying drawings wherein:

FIG. 1 is a cross sectional view of one embodiment of this invention;

FIG. 2 is a cross sectional view of another embodiment of thisinvention;

FIG. 3 is an exploded view of a penile insert according to the inventionand its container;

FIG. 4 is a side view, partly in section, of an inserter/containerassembly for introducing a composition containing a dose of agent intothe urethra;

FIG. 5 is a top view of the inserter/container of FIG. 4;

FIG. 6 is a side view of another inserter construction for introducing adose into the urethra;

FIG. 7 is a cross-section through the inserter of FIG. 6 in the fillingposition; and

FIG. 8 is a cross-section through the inserter of FIG. 6 in the loadedposition.

DESCRIPTION OF THE INVENTION INCLUDING THE BEST MODE

In its broadest aspect, this invention contemplates the treatment oferectile dysfunction by the transurethral administration of an agent,therapeutically effective with respect to the dysfunction, directly intothe blood supplying the corpus cavernosum via the cross circulation withthe spongiosa surrounding the urethra. The erectile dysfunctions whichmay be so treated include impotence, for which the therapeutic agent isone or more drugs capable of producing a vaso-dilatory or other erectioninducing effect. Suitable vaso-dilatory agents include nitrates such asnitroglycerin and isosorbide dinitrate, long and short acting α-blockerssuch as phenoxybenzamine, dibenamine, doxazosin, terazosin,phentolamine, tolazoline, prazosin and trimazosin; adenosine, ergotalkaloids, chlorpromazine, haloperidol, yohimbine, verapamil and othercalcium blockers, natural and synthetic vasoactive prostaglandins andanalogs thereof such as PGE₁, including alprostadil, misoprostol andenprostil, for example, prostaglandin E₂, minoxidil, vasoactiveintestinal peptides or any other agent which is capable of producing anerection when administered transurethrally. For example, dopamineagonists such as apomorphine and bromocriptine, testosterone, cocaine,strychnine, and opioid antagonists such as naltrexone have been reportedto induce erection and they may also be useful according to thisinvention. See S. Lal et al, Apomorphine: Clinical Studies on ErectileImpotence and Yawning, Prog. Neuro-Psychopharmacology, Vol. 13, 1989, pp329-339 and A. Fabbri et al, Endorphins in Male Impotence. Evidence forNaltrexone Stimulation of Erectile Activity in Patient Therapy,Psychoneuroendocrinology, Vol. 14, No. 1 & 2, pp 89, 103-111.

We have found that combinations of two or more drugs can exhibit asynergistic effect and preferred combinations are combinations ofα-blockers and prostaglandin particularly prazosin, doxazosin orterazosin with PGE₁, such as alprostadil, misoprostol or enprostil.

With respect to priapism, the therapeutic agent may be one or morevasoconstrictor drugs. Suitable vasoconstrictors include α-receptoragonists such as epinephrin, phenylethylamine, norepinephrine, dopamine,metaraminol, phenylephrine, methoxamine, ephedrine, phenylpropanolamine,mephentermine and propylhexedrine, for example, β-blockers such asbutoxamine, dichloroisoproterenol, propranolol, alprenolol, bunolol,nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, metoprolol,atenolol, acebutolol, bevantolol, pafenolol, and tolamolol, for example,and any other agent which is capable of producing a detumescent effectwhen applied transurethrally.

With respect to Peyronie's syndrome, the therapeutic agent may be one ormore anti-inflammatory drugs such as corticosteroids includingcortisone, hydrocortisone, tetrahydrocortisone, prednisone,prednisolone, methylprednisolone, fludrocortisone, desoxycortisol,corticosterone, triamcinolone, paramethasone, betamethasone,dexamethasone and beclomethasone, for example, non-steroidalanti-inflammatories such as salicylic acid, aspirin, diflunisal, methylsalicylate, phenylbutazone, oxyphenbutazone, apazone, phenacetin,acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamatesodium, tolmetin, ibuprofen, naproxen and fenoprofen, for example, andother drugs such as testosterone which may be capable of producing ananti-inflammatory effect on fibrous tissue within the corpus cavernosumwhen administered transurethrally.

It is preferred that the agent be rapidly delivered through the urethrain order to bring about a rapid onset of the desired effect. To that endthe agent containing material may be caused to contact the urethra alonga sizable portion, about 2-3 cm, of its length rather than localizing itat one site along the urethra. Also, the agent should be applied atleast 1 cm into the penis and past the point where the transition fromthe epidermal character of the glans has been completed. It has beenfound that rapid absorption can also be obtained when a small, rapidlyreleasing dosage form such as a gel, cream, ointment or suppository or acoating is deposited between the proximal portion of the fossanavicularis including the valves of navicularis and the distal portionof the pendulous urethra. This appears to be the optimum location forrapid absorption of the agent and although it varies from individual toindividual it is generally at a depth of 2-5 cm in the penis.

In all of the dosage forms contemplated herein, it is desirable that thevolume of agent-containing material that is deposited in the urethraremain within the urethra and in contact with the wall of the urethrauntil complete absorption of the agent has occurred and that thematerial be deposited in a manner that permits relatively rapidabsorption of the agent. Dosages in the range of 50-100 mg(approximately 50-100 μl in liquid volume) tended to exhibit observablespillage prior to complete absorption. Accordingly, the amount ofdrug-containing material retained in the urethra should be less thanabout 100 mg and preferably less than about 50 mg. Adequate lubricationhas been obtained with as little as 5-10 μl of lubricating carriers suchas polyethylene glycol (PEG) 1000 and 1450.

The dose of agent can be contained in any of the fluid or semi-fluidsolutions, suspensions, dispersions, ointments, pastes or gels selectedfrom the numerous formulations of such types known to the art butpreferably comprises a formulation in which the agent is dispersed in apharmaceutically acceptable carrier which rapidly releases the agentwithin the urethra. These formulations can also contain pharmaceuticallyacceptable antioxidants such as BHT, for example, and other stabilizingagents as is known to the art as may be required to extend shelf life.

Such a dose can be easily introduced into the urethra from a flexibletube, squeeze bottle, pump or aerosol spray single or multiple doseadministrator, for example. The agent may also be contained in rapidlyreleasing coatings or suppositories which are rapidly dissolvedabsorbed, melted or bioeroded in the urethra. Urethral permeationenhancers for the agent may also be included in the agent containingcompositions. In certain embodiments which are illustrated in FIGS. 1and 3, the agent is included in a coating on the exterior surface of apenile insert.

In the presently preferred embodiments of the invention, the agent iscontained in a dose of predetermined volume which is deposited as asuppository into the urethra at the desired location.

Referring now to FIG. 1, a penile insert 1 comprises a shaft portion 2which is sized to be easily and comfortably inserted into the maleurethra. Means are also provided to prevent complete insertion of theinserter into the urethra in a manner that would make removal difficult.The means may simply be a portion of the shaft of adequate length to begripped and not released during use. It is preferable however that theend of shaft 2 is provided with an enlarged terminal portion 3configured to prevent complete insertion into the urethra and tofacilitate removal of the device after the agent has been delivered. Theinternal end of shaft portion 2 is preferably provided with a rounded,blunted end to prevent discomfort on insertion and is typically fromabout 3 to 5 millimeters in diameter and from about 2 to 12 centimetersin length.

The insert itself may be made from any pharmacologically acceptablematerial and although it may be rigid, it is preferred that the devicebe relatively soft and flexible for purposes of comfort, merely havingsufficient rigidity to facilitate insertion. For this purpose variouspharmaceutically acceptable natural or synthetic rubber or polymericmaterials such as natural rubber, silicone rubber, ethylene vinylacetate (EVA) copolymers, polyethylene, polypropylene, polycarbonate,polyester, polyurethane, polyisobutylene polymers, and polyoxyethylenepolymers such as Delrin® manufactured by Du Pont, for example, aresuitable. Polypropylene is particularly useful, especially where theproduct is to be radiation sterilized.

Although the therapeutic agent and optionally a permeation enhancer maybe dispersed throughout the body of the insert 1, it is preferable thatthe agent be concentrated on the urethra-contacting surfaces of thedevice in order to permit rapid absorption of the agent and anypermeation enhancer. As shown in FIG. 1, the shaft portion 2 of theinsert 1 is provided with an agent-containing coating 4 which comprisesthe desired agent dose and, if used, a permeation enhancer, dispersedthroughout a rapidly releasing carrier. The coating 4 may be applied tothe insert by means of dip coating in an appropriate agent-containingbath, spray coating, heat melt coating, evaporation of a fixed volume ofa solution or suspension of the agent in a volatile vehicle or byco-extrusion of an agent-containing layer onto the surface of shaft 2,for example.

To facilitate insertion, coating 4 preferably has lubricating propertiesand may contain dispersant materials such as PEG, propylene glycol,glycerine, polyvinyl pyrrolidine (PVP), polyvinyl alcohol (PVA), hydroxyalkyl celluloses or cyclodextrins, for example, which are or becomeslippery upon insertion into the urethra. Materials such as glycerolmonolaurate, polyethylene glycol monolaurate, and glycerol monolaurate,for example, may combine permeation enhancing properties withlubricating properties.

To facilitate adherence of the drug coatings to the penile insert, thesurfaces to which the coatings are applied may be slightly roughened.Also, to provide a visual indication of complete agent release, thecoating, instead of being clear and transparent, can be selected toprovide a different visual appearance from that of the uncoated insert.This can be accomplished with the use of dyes or pigments or can be aproperty of the agent or coating material itself.

In use, the device would be inserted slowly (about 5-10 seconds) intothe urethra up to the terminal portion 3 and either maintained in placeuntil the agent is absorbed (about 30-35 seconds) and then slowlyremoved, or more preferably, particularly with shorter devices (about2-5 cm in length), the device 1 would be inserted into the urethra up toportion 3 and then, while compressing the penis around shaft 2, gentlybut firmly rotated and reciprocated to wipe all the agent-containingmaterial from the surface of the device prior to removal.

When the agent dose is formed from a water soluble material such as PEGit is also preferable that the patient urinate shortly beforeadministration of the dose. The residual urine in the urethra cause thedose to dissolve more rapidly producing more rapid drug absorption.

Referring now to FIG. 2, a combination insert/container 10 is shown inwhich the insert 11 is provided with a tapered agent-carrying shaftportion 12 which terminates in a plug portion 13 which may also beprovided with sealing ridges 13a. Plug element 13 terminates in capportion 14 which may be larger than plug 13 and preferably of a squareor other polygonal configuration to make it easy to rotate insert 11 forremoval from its container 15. Container 15 is generally tubular inshape closed at one end and of sufficient length to receive the insertup to contact with cap 14. The interior diameter of container 15 and theexterior diameter of plug 13 with sealing ridges 13a are selected toprovide a sliding seal that is sufficient to prevent insert 1 fromfalling out of the container and the passage of contaminants into thecontainer while permitting removal of the insert with the application ofa reasonable force on cap 14.

Referring now to FIG. 3, another embodiment of the invention is shown inwhich the penile insert 20 comprises a shaft portion 22 adapted to bereceived within the male urethra and a terminal portion 23 in the formof a tubular cap adapted to enclose the glans and, if more agentdelivering surface is required, some portion of the shaft of penis 17.The body-contacting surface of insert 20 is provided with anagent-containing coating 24 similar to that described with respect toFIG. 1 which coating is applied to the shaft 22 and such other portionof the interior of the terminal portion 23 as is desired. The embodimentof FIG. 3 may be used with respect to less potent agents which requirean administration rate greater than can be obtained directly through theurethra. Thus the portion of the coating 24 which contacts the glans andthe shaft of the penis also provides for the administration of the agentdirectly through the skin of the penis in addition to the transurethraladministration.

In use, the device would be inserted into the urethra 16 and in contactwith the skin of penis 17 and maintained in place until all the agenthas been released from coating 14. In FIG. 3 a constrictive, typicallyelastic, band 18 is applied around the base of the penis 17 while theinsert 20 is in place to constrict the penis and prevent the flow ofblood therefrom. This constrictive band can also be used with respect tothe embodiments of FIGS. 1, 2, 4 and 5. It is useful in impotence whereit will prevent the flow of blood from corpus cavernosum therebyassisting in the maintenance of the erection and in Peyronie's syndromewhere it will cause the anti-inflammatory drug to remain in the corpuscavernosum for an extended period of time. The constricting bands wouldnot normally be used when the device of this invention is used to treatPriapism where it is desired to increase, rather than retard, the flowof blood from the penis.

In the practice of this invention it is desirable that the entire doseof the agent be reproducibly deposited in contact with the urethra atthe desired location within the urethra. Because the coatings on theinserts of FIGS. 1-3 are in contact with the urethra during theinsertion and removal procedure, it is possible that some of the coatingmay be deposited at non-optimum locations or that all of the coating maynot be removed prior to withdrawal of the insert. In order to obtain amore precise control of the dose administered and the site ofapplication, the dose can be contained within the insert where it isprotected from contact with the urethra during insertion and means canbe provided to positively displace the entire dose from the insert intothe urethra at the desired depth of application.

Referring now to FIGS. 4 and 5 another embodiment of this invention isshown for use when the agent is contained in an ointment, paste,suppository, cream or gel formulation of the type described above ratherthan as a coating on the shaft of an inserter. The dosageinserter/container 25 comprises a container 26 closed at one end andreceiving inserter 27 in the other end. Although container 26 can becylindrical in configuration it is preferred to form container 26 into amore volume efficient flattened configuration such as elliptical orrectangular because there is no need to maintain a large clearancebetween the exterior of inserter 27 and the interior of container 26, toprevent inadvertent removal of any coating on inserter 27. Inserter 27comprises a shaft portion 28 having an external configuration similar tothat of the inserter shown in FIGS. 1 and 2 but provided with alongitudinal bore which receives the piston portion 29 of plunger 30,the agent-containing dose 31 in the form of an ointment, paste,suppository, cream or gel having sufficient viscosity to enable it toremain, without spillage, within the cavity formed between the tip ofpiston 29 and the end of the bore. The bore may communicate with theurethra through the single outlet shown in FIG. 4 through which the doseis ejected by movement of piston 29. Alternatively, the end of theinserter could be provided with a multiplicity of small holesdistributed about the tip through which the dose could be extruded insmall streams into contact with the urethra.

Preferably, means are provided to prevent unintentional activation ofplunger 30 which in its simplest form could be a frangible bead or bondwhich resists relative motion of plunger 30 with respect to shaftportion 28 until a predetermined force is applied. A more positive meansis illustrated in FIGS. 4 and 5 wherein shaft portion 28 terminates in aplug portion 32 configured to form a sliding seal with the interior ofcontainer 26. The plug portion 32 terminates in cap portion 33 providedwith receptacle means 34 configured to receive plunger 30 when plunger30 is in a first position and to be incapable of receiving plunger 30when in a second position and being of sufficient depth to allowdisplacement of piston 29 over sufficient travel to fully displace dose31 from the inserter. In FIGS. 4 and 5 the receptacle 34 is shown as aslot across cap 33. Plunger 30 is mounted transverse to slot 34 andmaintained in this first position by a frangible bond 35. Cap 33 islikewise sealed to container 26 by a similar frangible bond 36. Thesefrangible bonds can be formed by any suitable technique which includeadhesive bonding, heat or sonic welding or the application of some formof "shrink wrap" material, for example.

This configuration is readily adaptable to automated filling togetherwith precise control of the quantity of dose 31 and provides forpositive administration of the desired quantity of agent at the desiredsite of application.

Prior to use the device is protected from inadvertent displacement ofdose 31 by means of the frangible seal 35 and inadvertent removal of theinserter by means of frangible seal 36. In use, frangible seal 35 wouldbe broken by rotating plunger 30 from its first position to a secondposition where it is in alignment with receptacle 34 and frangible seal36 would be broken to remove the inserter 27 from container 26. Theinserter would then be placed into the urethra to the depth of plug 32and plunger 30 depressed into receptacle 34 to completely eject dose 31into the urethra at the desired point of application. The inserter 27would then be removed leaving the dose 31 within the urethra.

The materials used to form the inserter/container 25 are the same asthose which can be used in fabricating the devices of FIGS. 1 and 2 forexample and when these materials are thermoplastic the formation of thefrangible bonds 35 and 36 by sonic fusion is a preferred technique.

In order to assure the complete displacement of dose 31 by piston 29,relatively precise tolerances must be maintained with respect to theinternal and external diameters of the bore through shaft portion 28 andof the piston 29, respectively. FIGS. 6, 7 and 8 describe a device inwhich manufacturing tolerances can be more relaxed while stillmaintaining positive displacement of the entire dose to the urethra atthe desired position. Inserter 40 of FIGS. 6, 7 and 8 comprises a sleeve41 which is preferably slightly thinner or otherwise weakened about theperiphery of its distal end 42 such that this portion is more flexiblethan the remainder of sleeve 41 so that it will deform preferentially atthis location. Sleeve 41 is also preferably provided with a thickenedterminal portion 43. Sleeve 41 is sized to be received within the maleurethra and preferably terminates at a shoulder 44 on handle 45,shoulder 44 being of sufficient diameter to prevent insertion into theurethra. Sleeve 41 may be formed as a unit with handle 45 or it may beformed separately and bonded or otherwise attached to shoulder 44.Handle 45 is provided with a central bore having a diametercorresponding to the interior of sleeve 41 and piston 46 is slidablyreceived within sleeve 41 and handle 45. The distal end of piston 46 isfirmly connected to the interior portion of the end portion 43 of sleeve41. When piston 46 is moved to a position where it completely fillssleeve 42, the inserter has the configuration shown in FIG. 6. However,when piston 46 is withdrawn slightly from the position of FIG. 6, theend 43 of sleeve 41 will be withdrawn with the piston to form a cupshaped cavity into which a suppository 47, preferably spherical,comprising the agent dose can be received. Upon further withdrawal tothe position shown in FIG. 8, the peripheral portion 42 of the end ofsleeve 41 will have been withdrawn by piston 46 into the sleeve 41causing it to surround and envelope suppository 47.

In operation, the spherical suppositories 47 would be fabricated in thefrozen condition by any of the conventional techniques used for themanufacture of spherical granules of predetermined size. Equipment formanufacturing small spherical particles is known to the art and includesrotary processing, multiple-step extrusion and spheronization equipment.Suitable equipment is available, for example, from Niro-Aeromatic, Inc.of Colombia, Md.

To load the inserter, piston 46 would be moved to the position shown inFIG. 7 and the frozen suppository 47 deposited in the cup shapereceptacle so formed. The piston 46 would then be withdrawn to theposition shown in FIG. 8 completely enclosing and enveloping thesuppository 47 within the retroverted tip 42 of the sleeve. In use, theloaded inserter would be inserted into the male urethra until shoulder44 abuts the meatus and plunger 46 moved forward to the position shownin FIG. 6 thereby releasing suppository 47 from the tip of the inserterand depositing it at the desired depth.

Inserter 40 may be made from any of the materials described inconnection with the embodiments of FIGS. 1-4 and may be provided withmeans for preventing inadvertent actuation as described with respect toFIGS. 4 and 5. For example, after the inserter is loaded with thesuppository as shown in FIG. 8, sonic bonds could be formed between thehandle 45 and the piston 46 or a cap-like structure similar to that ofFIGS. 4 and 5 could be employed.

Although the configurations shown in FIGS. 4-8 are preferredconfigurations, other inserter/container configurations can be used andany mechanism by which a predetermined quantity of drug can beintroduced from the inserter at a predetermined depth in the urethra issuitable for use with this invention. As with the other devices of thisinvention, the agent in dose 31 can be one or more drugs. However, whena combination of drugs is required to produce the desired therapeuticeffect, it is also possible to sequentially administer separate doses ofeach individual drug, each of which can then be titrated by thephysician and/or patient to produce the desired effect.

The embodiments of this invention can either be manufactured understerile conditions thereby eliminating the need for post manufacturingsterilization or they can be manufactured under non-sterile conditionsand then subsequently sterilized by any suitable technique such asradiation sterilization.

The penile inserts and injectors of this invention can be manufacturedby typical plastic forming and coating process and solvent evaporationknown to the art which include molding, extrusion, heat forming, dipcoating, spray coating, heat melt coating and solvent evaporation.Although prototype devices of FIG. 1 were made from EVA rods which wereheat formed by hand into the configuration of FIG. 1 on a hot plate toflatten the exterior end and blunt the interior end, components formingthe various embodiments of this invention can be made in quantity inconventional injection molding equipment.

Molded parts which require coating can be coated by any suitableprocess. Dip coating, with control of the temperature and viscosity ofthe bath and the dwell time of the article to be coated in the bath,coupled with air wiping for added precision is capable of producingquite reproducible coatings within the requirements of this invention.Depositing a known volume of a solution or suspension of theagent/dispersant in a volatile carrier onto the shaft in the presence ofa warm air stream also produces coating in a reproducible manner as doesthe application of a known volume of a melt containing the agent to acool inserter shaft.

PEG based coating and suppository formulations are particularly suitableto this invention because they are solid at refrigerator or ambienttemperatures, have lubricating properties, dissolve in the urethra toallow rapid absorption of the active agent therein dispersed and somelower molecular weight PEGs also melt at urethral temperatures.

PEGs of varying molecular weight from about 400-8000 including mixturesof PEG can be used according to this invention. All PEGs will dissolvein the urethra whereas only the lower molecular weight species willmelt. Temperatures in the flacid penis are normally in the range of30°-32° C., at or above the melting point of PEGs up to about molecularweights of 600. PEG 1000 melts at about 37°-40° C. PEG 1450 melts atabout 43°-46° C. and higher molecular weight PEGs melt at highertemperatures. PEGs as a class, are highly water soluble, about 70-80% byweight in water at 20° C. and even higher at the temperatures within theurethra.

At 70° C. the viscosity of a 50--50 blend of PEG 1450 and PEG 400 issuch that approximately 100 mg of a dip mixture was reproducibly left ona 10 cm long by 3.5 mm diameter EVA rod after a single dip. By varyingthe molecular weight of the PEGs and/or their ratios and/or thetemperature of the bath, the viscosity of the bath and the resultantweight of the coating can be adjusted. For example, a 1:2 weight ratiomixture of PEG 600 and PEG 1000 will have a melting point of about 32°C. and could be expected to yield a coating of approximately 50 mg at abath temperature within the range of about 50°-80° C.

PEG 1450 is available as a flake material at room temperature which onmelting and cooling forms a smooth coating on the insert of thisinvention. At bath temperatures in the range of 60° C. to 80° C.coatings of about 50 mg can be obtained from a single dip.

As another example, at 70° C., PEG 1450 deposited on the 2 cm of the tipequals about 50 mg. The slower dissolution of the higher molecularweight PEG allows controlled deposit on a limited area. As the system isinserted into the urethra the slower melt of PEG 1450 allows minimaldeposition in the distal urethra and maximum at the depth of fullinsertion.

Doses such as coatings and suppositories formed from the lower molecularweight PEGs need to be stored under refrigeration when high ambienttemperatures are anticipated. Doses formed from PEG 1450 and above,however, have physical stability even when carried exposed to highsummer temperatures.

Another approach to forming the desired coating on the shaft 12 of theinserter is to micropipette a known quantity of the agent and dispersantin solution or suspension in a volatile solvent onto the shaft 12 whichis maintained in a downwardly inclined position in the presence of awarm air stream to permit rapid evaporation of the solvent before any ofthe liquid can drop from the shaft. This approach is particularlysuitable when both the agent and the dispersant are mutually soluble inthe volatile carrier.

As an example, PGE₁, together with a lubricating dispersant such aspropylene glycol, PEG, glycerin, PVP, PVA, cyclodextrin or hydroxyalkylcellulose for example, would be dissolved in weight ratios of dispersantto agent of 1:1-10:1 in alcohol at a concentration such that a smallvolume, approximately 10 μl for example, of the alcoholic solutioncontains the desired dose of the agent. This predetermined quantity ofsolution would be introduced from a micropipette onto the surface of theinserter in the presence of a warm air stream and would evaporaterapidly to form the desired coating. The volume of solution is notcritical but should be selected based on the size of the insert and theviscosity of the solution such that a relatively even coating of thesolvent solution on the shaft is obtained without any spillage prior toevaporation of the volatile solvent. Melted PGE, containing the agentcan also be micropipetted in a similar manner onto a cool inserter shaftto provide reproducible doses of single or multiple drugs.

Preferably, the total weight of the dose should be minimized consistentwith the maintenance of lubricating properties. At about the 50-100 mglevel, the capacity of the urethra to receive and retain the agentcontaining dose and rapidly absorb the agent appears to be reached assome spillage of the dose was observed. Accordingly, dose weights shouldbe less than about 100 mg and preferably less than about 50 mg. Similaramounts are contemplated whether the dose is in the form of a coating oris in the form of a solution, dispersion, ointment, paste, gel orsuppository, for example.

Once the weight of the agent-containing dose or coating has beenselected, the concentration of the agent in the carrier would beappropriately selected to provide the desired total dose within thedosage form or coating.

Unit dosages for PGE₁, are in the range of about 10 to 2000 μg, about 50to 500 μg being preferred, the unit dosages of papaverine are in therange of about 1-50 mg, and the unit dosages of phentolamine are in therange of about 1-10 mg, and the unit dose of prazosin, doxazosin andterazosin are in the range of about 50-2000 μg per dose with 100 to 1000μg being preferred. It has been observed that combinations of two ormore drugs such as PGE₁, ie, alprostadil, misoprostol or enprostil withα-blockers, ie, prazosin, doxazosin or terazosin tend to potentiate theerectile effect thereby permitting efficacy to be obtained at lowerdoses of both drugs.

If the agent is a combination of drugs they all may be included in onedosage form. However, when the agent comprises more than one drug, itwould be preferable to sequentially administer each drug from a dosageform containing only one drug.

It is always preferred to use the lowest effective dose in any medicalintervention and it is contemplated that the dosage forms of thisinvention would be provided in various, incremental doses. The patientwould initially titrate himself to the dosage effective for him by usingthe lowest dosage, and repeating administration until the desired effectis obtained. Thereafter the patient would select an effectiveincremental dosage that is close to the determined higher dosage orcould continue using multiple lower doses.

The following examples of this invention are provided.

EXAMPLE 1

A 3.5 mm EVA (28% VA) rod was formed into an insert having a shaftapproximately 10 cm long with a spherical, blunted tip and a headportion approximately 4 mm thick and 1 cm in diameter on a hot plate. Adipping bath comprising a 50--50 weight blend of PEG 1450 and PEG 400and sufficient agent to attain the desired concentration in 100 mg ofcoating was prepared and heated to 70° C. The insert suspended by itshead, was dipped into the dipping bath and removed.

The total weight of the coating so obtained was approximately 100 mg.Nine inserts having coatings containing approximately 50 μg of PGE₁ andnine inserts having coatings containing approximately 50 μg PGE₁ and 100μg prazosin hydrochloride were prepared. When used by an impotent humanvolunteer, four doses of the 50 g PGE₁ were required to achieve minimalerection. The dosage forms combining PGE₁ and prazosin produced astronger erection in both normal and impotent volunteers at a lowertotal dose of two units in a shorter period of time. A slight burningsensation in the urethra was observed by the normal volunteer with thedevices using the prazosin hydrochloride but not by the impotentpatient. The use of the base form of prazosin rather than thehydrochloride may eliminate the sensation.

EXAMPLE 2

A 3 mm diameter EVA (24% VA) rod approximately 10 cm in length wasblunted and rounded on one end and flattened on the other bymanipulation on a hot plate. A gelled aqueous coating formulation,comprising 9 gm of 95% ethanol, 1 gm of propylene glycol, 0.2 gm ofhydroxypropyl cellulose and 2 mg of PGE₁ was prepared and dip coated onthe shaft of the rod to a total loading of about 500 mg. The residualethanol in the coated rod was allowed to evaporate. It is estimated thatthe loading of PGE₁ was about 200 μg/unit. Penile erection was producedin a normal human subject within ten minutes after the sequentialinsertion of two rods into the urethra for a total PGE₁ dose of 400 μg.

EXAMPLE 3

A 3.5 mm EVA (28% VA) rod approximately 10 cm long with rounded tip andflattened head is coated with 500 μg of prazosin base in a PEG blend(1:2 PEG 600:PEG 1000) having a melting point of approximately 32° C.Initial tumescence should be achieved within several minutes afterinsertion into the male urethra with maximum effect being producedwithin about fifteen minutes. Both the intensity and duration of effectwill be greater in patients with normal vasculature whose impotence isdue to neurologic deficiency. With marked vascular damage a single drugmay have incomplete action requiring additional doses or the use of amixed drug formulation.

EXAMPLE 4

Penile inserts configured as in Example 3 are coated with a mixture of20 μg of PGE₁ and 200 μg of doxazosin hydrochloride in the PEG mixturedescribed in Example 3. Patients with moderately severe vasculardeficiencies should attain erectile response from this dosage in severalminutes which should be maintained for approximately thirty minutes.

EXAMPLE 5

Penile inserts configured as in Example 3 are coated with 100 μg ofphenylephrine in approximately 50 mg of the PEG mixture of Example 3 orapproximately 100 μg of adrenalin contained in the PEG mixture ofExample 3. Inserts so fabricated are inserted into the urethra of apatient suffering from priapism, due either to pharmacological or othercauses. If detumescence is not obtained within approximately five to tenminutes the application will be repeated at approximately ten minuteintervals until detumescence occurs. Small incremental doses areadministered in this fashion to prevent systemic overdosage whenbalanced circulation is reestablished.

EXAMPLE 6

Penile inserts configured as in Example 3 are coated with 100 μg oftriamcinolone acetonide in approximately 50 mg of the PEG mixture ofExample 3 and in 50 mg of PEG in the molecular weight range of about2000-8000 or 50 μg of fluocinonide in approximately 50 mg of the PEGmixture of Example 3 and in 50 mg of PEG in the molecular weight rangeof 2000-8000. Such inserts are inserted daily into the urethra of apatient suffering from Peyronie's disease and allowed to remain in theurethra for approximately twenty minutes to provide the steroid intherapeutic local concentration in the corpus cavernosa. This methodeliminates the trauma associated with the local injection of theanti-inflammatory agent which may in itself stimulate the fibroticprocess which the therapeutic agent is intended to correct. Ifimprovement is not observed after a course of treatment with singledoses, multiple doses can be used for twenty minutes each until a dosagelevel which is effective can be established.

EXAMPLE 7

Penile inserts as in FIG. 1 are dip coated with a mixture of PEG 1450 ata temperature of 70° C. containing 1% PGE₁. Dipping to a depth of 2 cmin such a solution leaves a total mass of 50 mg on the distal 2 cm andcontains 500 μg of PGE₁. The dipping time is about 1 second and coolingtime 3 minutes at room temperature of about 20° C.

This system was stable when carried exposed to summer temperatures inWashington, D.C. and provided adequate lubrication upon insertion wheninserted slowly over a period of approximately 5-10 seconds.Approximately 30 seconds after full insertion the system was then slowlyremoved over 10 seconds, the entire coating had been released into theurethra after this procedure. Erection was obtained after about 15minutes in a normal male.

EXAMPLE 8

A penile insert configured as shown in FIG. 2 was injection molded toprovide a shaft portion 12 approximately 3 cm in length having a taperfrom approximately 3 mm diameter at the plug end to approximately 2.5 mmat the tip end was injection molded from polyoxymethylene polymer. PGE₁together with an equal weight amount of propylene glycol as alubricant/dispersant were dissolved in ethyl alcohol at a concentrationof 400 μg PGE₁ per 10 μl of solution. Ten μl of this solution weredispensed from a micropipette onto the shaft portion of the insert,inclined approximately 45° from the vertical, in the presence of warm,flowing air to evaporate the alcohol and provide a thin coating of thePGE₁ in the dispersant on the shaft of the insert. The insert was thenplaced within its container. The insert was inserted into the urethraand vigorously rotated and reciprocated to wipe the PGE₁ from thesurface of the insert for approximately 20 seconds. Similar inserts wereused by two other subjects and functional erections were obtained inapproximately 10 minutes and lasted for approximately 30 minutes. Thisproduct exhibited a relatively short shelf life, possibly due toinstability of the PGE₁ in the presence of moisture. It would thereforebe preferred to manufacture and package the device in a low humidity ornitrogen environment.

EXAMPLE 9

A penile insert was manufactured as described in Example 8 except thatthe drug alprostadil (PGE₁) was mixed with a gamma type cyclo- dextrinat a ratio of 1 part alprostadil to 4 parts cyclodextrin. This productmay have a longer shelf life than the product of Example 8.

EXAMPLE 10

Inserts configured as shown in FIGS. 1 and 2 have been evaluated inimpotent males in which the impotence is associated with diabetes,post-coronary bypass (vascular insufficiency) and a post-radicalprostatectomy, normal aged males and normal healthy males using variousvasoactive drugs and combinations thereof. In all instances patientshave responded positively although variations in intensity of erectionand duration thereof were observed depending on dose, formulation andenvironment. Analysis of returned used systems showed residual drugloadings of from 0-50% indicating that application technique isimportant in use of the inserter. The preferred insertion techniquewhich is associated with substantially complete drug removal from theinserter involves slow insertion to the maximum depth over a period of5-10 seconds, followed by reciprocation and rotation of the inserterover approximately a 2-3 cm length while maintaining pressure on thepenis to maintain intimate contact between the urethra and the shaft ofthe inserter for about 20 seconds and then slow removal of the inserterwhile maintaining compression on the penis. This technique effectivelywipes the surface of the inserter clean and provides for substantiallycomplete agent delivery.

EXAMPLE 11

An inserter configured as in FIG. 4 was injection molded to provide ashaft portion approximately 3 cm in length having a taper fromapproximately 3 mm diameter at the plug end to approximately 2.5 mm atthe tip end provided with a 1.5 mm central bore. The plunger is insertedinto the central bore to a depth that leaves a 1.5 mm long cavity at thetip. The inserter is inverted and melted PEG 1450 containing 400 μg ofalprostadil is cast into the cavity and solidified therein. Uponsolidification, a suppository weighing about 2.9 mg and containing about15% wt alprostadil was formed. Alternatively, a suppository in the formof a 1.5 mm long cylinder of solid PEG 1450 containing 400 μg ofalprostadil could be introduced into the shaft either at the tip ormoved to the tip of inserter when the plunger is introduced into the 1.5mm bore. The inserter is molded from polypropylene. The inserter is thenplaced within a polypropylene container and a sonic bond is formedbetween the plug portion of the inserter and the container and betweenthe plunger which is mounted crosswise to the slot in the cap. Thedevice may then be radiation sterilized. In use, the bonds between theplunger and the cap and the cap and the container would be broken andthe inserter assembly removed from the container, the plunger would berotated into alignment with the slot in the cap, the shaft of theinserter would be inserted into the penis up to the beginning of theplug and the plunger depressed into the slot to inject the agent loadinto the urethra. The device would then be removed.

EXAMPLE 12

Suppositories similar to those of Example 11 can also be formed invarying dosages to permit titration to meet the requirements ofindividual patients. For example, suppositories can be formed containing100 μg, 300 μg, 500 μg and 700 μg of alprostadil dispersed in PEG 1000or 1450 at a loading of about 15% by weight. The PEG 1000 appears todissolve in the urethra more rapidly than the PEG 1450 and is presentlythe preferred PEG. The 100 μg dose is presently preferred for paraplegicpatients and the 500 μg dose is presently preferred for normal patients.The 300 μg and 700 μg doses are available for titration upward ordownward to meet an individual patients requirements and, if required,various combinations of these dosages could be administered sequentiallyto provide an even greater number of available doses. Since the densityof the PEG-alprostadil formulations are about 1.1 mg/m³ the variousdosages can be obtained quite simply by changing the length of thepiston 29 of FIG. 4. Thus, to obtain suppositories 1.5 mm in diametercontaining 100 μg, 300 μg, 500 μg and 700 μg of alprostadil, the lengthof the piston would be selected to form suppositories 0.375 mm, 1.125mm, 1.875 mm and 2.625 mm in length, respectively.

EXAMPLE 13

Dosage forms comprising a mixture of the agents alprostadil and prazosinwere made by depositing approximately 10 μl doses of molten PEG 1450containing the amounts of alprostadil shown below onto the tip of aninserter having a 3 cm long shaft and allowed to cool. Thereafterapproximately 10 μl doses of molten PEG 1450 containing the amounts ofprazosin shown below were deposited onto the tip and allowed to cool.All inserts produced sexually functional erections in 4 differentimpotent subjects.

                  TABLE 1                                                         ______________________________________                                        Sample #    μg Alprostadil                                                                        μg Prazosin HCl                                     ______________________________________                                        1           238        718                                                    2           216        412                                                    3           255        505                                                    4           230        437                                                    5           200        430                                                    ______________________________________                                    

EXAMPLE 14

An inserter configured as in FIGS. 6-8 is fabricated from polypropylenein which the sleeve portion 41 is 3 cm in length and approximately 3.5mm in external diameter having a wall thickness of about 0.3 mm. Theperipheral portion 42 of the sleeve 41 is of a reduced thickness ofabout 0.1 mm and the thickened portion 43 is about 0.5 mm in thickness.A suppository 47, in the form of a sphere of PEG 1450 approximately 2.5mm in diameter and containing 300 μg of alprostadil and 600 μg ofprazosin, will weigh approximately 5 mg. Such device can be used in thetreatment of impotence.

Having thus generally described our invention, it is obvious thatvarious modifications will be apparent to workers skilled in the artwhich can be made without departing from the scope of this inventionwhich is limited only by the following claims wherein:

We claim:
 1. A dosage form for treating an erectile dysfunctioncomprising a shaft sized to be received within the male urethra and acomposition retained within said shaft comprising an effective amount ofa vasoactive prostaglandin and at least one dispersant.
 2. The dosageform of claim 1 wherein said composition weighs not more than about 50mg.
 3. The dosage form of claim 2 wherein dysfunction is impotence andsaid agent consists of a mixture of from about 10-1000 μg of alprostadiland 50-1000 μg of prazosin.
 4. The dosage form of claim 1 wherein saidcomposition comprises a urethral permeation enhancer for said agent. 5.The dosage form of claim 1 wherein said agent comprises one or morevasodilators in addition to said vasoactive prostaglandin.
 6. The dosageform of claim 1 wherein said vasoactive prostaglandin is prostaglandinE₁.
 7. The dosage form of claim 1 wherein said vasoactive prostaglandinin prostaglandin E₂.
 8. The dosage form of claim 1 wherein saiddispersant is selected from the group consisting of pharmaceuticallyacceptable materials which dissolve, melt or bioerode within the urethrato release the agent.
 9. The dosage form of claim 5 wherein saidvasodilators are selected from the group consisting of nitrates, longand short acting α-blockers, calcium blockers, ergot alkaloids,chlorpromazine, haloperidol, yohimbine, vasoactive intestinal peptides,dopamine agonists, opioid antagonists and mixtures thereof.
 10. Thedosage form of claim 1 wherein said vasodilator is an α-blocker.
 11. Thedosage form of claim 5 wherein said agent comprises about 10-2000 μg ofa vasoactive prostaglandin and at least one vasodilator selected fromthe group consisting of about 1-50 mg of papaverine, about 1-10 mg ofphentolamine, about 50-2000 μg of prazosin, about 50-2000 μg ofdoxazosin about 50-2000 μg of terazosin and mixtures thereof.
 12. Thedosage form of claim 11 wherein said agent comprises about 10-2000 μg ofa vasoactive prostaglandin.
 13. The dosage form of claim 1 wherein saiddispersant is selected from the group consisting of polyethylene glycol,propylene glycol, glycerine, polyvinyl pyrrolidine, polyvinyl alcohol,hydroxy alkyl celluloses, and cyclodextrins.
 14. The dosage form ofclaim 1 wherein said dispersant comprises polyethylene glycol.
 15. Thedosage form of claim 1 wherein said dispersant comprises a cyclodextrin.16. The dosage form of claim 12 wherein said vasoactive prostaglandin isselected from the group consisting of natural and syntheticprostaglandins, prostaglandin E₁, alprostadil, misoprostol, enprostil,prostaglandin E₂, and analogs thereof.
 17. The dosage form of claim 11wherein said agent consists essentially of alprostadil and prazosin. 18.The dosage form of claims 1 wherein said composition is present in anamount less than about 100 mg.